PROJECT SUMMARY/ABSTRACT Intracellular infections based in the lung alveolar macrophage population remain one of the most challenging anti-infective settings and unmet medical needs. Diseases such as tuberculosis, legionellosis, tularemia and melioidosis cause high mortality and morbidity costs around the globe. The long-term goal of this project is to develop and validate a new inhalable macromolecular therapeutic platform termed ?drugamers? that targets antibiotics and antibiotic drug combinations to the alveolar macrophage to better treat lung-based intracellular infections. A key new property of this platform, that currently does not exist in clinically available therapeutics and delivery systems, is the ability to engineer custom tailored pharmacokinetic (PK) drug release profiles in the alveolar compartment and targeted alveolar macrophages that match the required PK profiles of specific antibiotic classes and specific bacterial infection processes. To achieve this objective, the project brings together a multi-disciplinary team across polymer therapeutics, glycan targeting of alveolar macrophages, and clinical expertise in alveolar-based bacterial pathology and treatment. The initial therapeutic focus is on tularemia and melioidosis, with clinical investigators and access to BSL-3 human pathogen models and facilities. The proposal is structured around 4 specific aims to: (1) Synthetically construct mannose-targeted drugamers of fluoroquinolone, ?-lactam, and aminoglycoside drugs and drug combinations with controlled release profiles and architectural morphologies designed to optimize alveolar macrophage uptake. (2) Optimize the biocompatibility, alveolar macrophage targeting, and PK properties - measured by liquid chromatography ? mass spectrometry analysis - of the drugamer library in murine models based on known drug dosing profiles of these major classes of antibiotics. Select optimized drugamers based on these in vivo properties to carry forward into the surrogate models of tularemia and melioidosis of the next aim. (3) Evaluate in vivo bactericidal efficacy of the mannose-targeted drugamers selected through their winning properties in Aim 2. Drugamers administered by aerosoloization will be tested for their ability to achieve cures in highly lethal mouse disease models infected by controlled aerosolization of surrogate Francisella and Burholderia bacteria. (4) Highly effective drugamer designs selected in Aim 3 will be assessed in human pathogen mouse models using Francisella tularensis and Burkholderia pseudomallei at the University of Washington BSL3 select agent facility. If successful, this project will identify lead inhalation therapeutics for future clinical pathway development against tularemia and melioidosis. Because the drugamer platform is modular, it could also be developed against other unmet intracellular lung infection therapy needs, where the growing issue of drug resistance provides a compelling need for the tailored and combination dosing profiles of this platform.